Benzenesulfonyl ureas and process for their manufacture

ABSTRACT

N-(4-( Beta - benzamido-ethyl)-benzenesulfonyl)-N&#39;&#39;(endoalkylene-cyclohexyl- or cyclohexenyl)-ureas being substituted at the benzamido group and having hypoglycemic activity.

Weber et al.

' United States Patent [1 1 [4 1 *Nov. 4, 1975 BENZENESULFONYL UREAS AND PROCESS FOR THEIR MANUFACTURE Inventors:

Assignee:

Notice:

Filed:

App]. No.:

Hoechst Aktiengesellschaft, Frankfurt am Main, Germany The portion of the term of this patent subsequent to July 8, 1986, has been disclaimed.

Feb. 2, 1971 Related US. Application Data Continuation of Ser. No. 681,116, Nov. 7, 1967,

abandoned.

[52] US. Cl. 260/553 DA; 424/322 [51] Int. Cl. C07C 127/16 [58] Field of Search 260/553 DA [56] References Cited UNITED STATES PATENTS 3,448,149 6/1969 Aumiiller 260/553 DA 3,454,635 7/1969 Weber et al. 260/553 DA FOREIGN PATENTS OR APPLICATIONS 654,561 4/1965 Belgium 260/553 D Primary ExaminerGerald A. Schwartz Attorney, Agent, or FirmCurtis, Morris & Safford [57] ABSTRACT N-[4-(B- benzamido-ethyl)-benzenesulfonyl]-N'- (endoalkylene-cyclohexylor cyclohexenyl)-ureas being substituted at the benzamido group and having hypoglycemic activity.

11 Claims, N0 Drawings BENZENESULFONYL UREAS PROCESS FOR THEIR MANUFACTURE This application is a streamlined continuation of Ser. 5

which as such or in the form of their physiologically tolerable salts show hypoglycemic properties and are characterized by a strong hypoglycemic action.

In the formula R represents lower alkyl, preferably methyl or lower alkenyl,

X represents hydrogen, fluorine, chlorine or bromine, preferably chlorine, lower alkyl, preferably methyl or lower alkoxy, preferably methoxy,

R represents endomethylene-cyclohexyl, endomethylene-cyclohexenyl, endoethylene-cyclohexyl, endoethylene-cyclohexenyl. The substitutent X is in 4- or preferably in 5-position to the carbonamide group.

In the above and the following definitions lower alkyl, alkenyl or alkoxy always stands for an alkyl, alkenyl or alkoxy group containing 1 to 4 carbon atoms in a straight or branched chain.

According to the above-mentioned definitions R may represent, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, allyl.

In particular R may represent 2.5-endomethylenecyclohexenyl, 2.S-endomethylenecyclohexyl, 2.5-endoethylenecyclohexyl, 2.5-endoethylenecyclohexenyl.

The present invention relates furthermore to a process for the preparation of said benzenesulfonyl-ureas wherein a. benzenesulfonyl-isocyanates, benzenesulfonyl-carbamic acid esters, benzenesulfonyl-thiolcarbamic acid esters, benzenesulfonyl-carbamic acid halides or benzenesulfonyl-ureas, benzenesulfonyl-semicarbazides or benzenesulfonyl-semicarbazones substituted in p-position by the group are reacted with R -substituted amines or, if desired, the salts thereof,

b. benzenesulfonamides of the formula or their salts are reacted with R -substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas,

c. correspondingly substituted benzenesulfonylisourea ethers, benzene-sulfonyl-isourea esters, benzenesulfonylisothiourea ethers, benzenesulfonyl-parabanic acids or benzenesulfonyl-haloformic acid ami dines are hydrolyzed,

a. correspondingly substituted benzenesulfonylhalides are reacted with R -substituted ureas, in particular their alkaline metal salts,

e. correspondingly substituted benzenesulfinic acid halides or, in the presence of acid condensing agents even correspondingly substituted benzenesulfinic acids or their alkaline metal salts, are reacted with hydroxy ureas the NH group of which being substituted by R,

f. to correspondingly substituted carbodiimides water is added,

g. in correspondingly substituted benzenesulfonylthioureas the sulfur atom is exchanged for an oxygen atom,

h. correspondingly substituted benzenesulfinyl-ureas or benzenesulfenyl-ureas are oxidized,

i. corresponding benzenesulfonyl-ureas containing in the molecule unsaturated linkages are hydrogenated,

k. in benzenesulfonyl-ureas of theformula the radical is introduced by acylation, if desired in several stages,

I. in correspondingly substituted thiobenzamidoalkylbenzene-sulfonyl-ureas or -benzenesulfonyl-thioureas the sulfur atom or the sulfur atoms are exchanged by an oxygen atom or oxygen atoms, or

I m. compounds of the formula or their parabanic acid derivatives or compounds of the formula Since this radial is split off during the reaction, its 2 chemical constitution has no influence on the character of the final product and can therefore vary within wide limits. The sameapplies to the R -substituted carbamic acid esters or the corresponding thiolcarbamic acid es- 2 ters.

As carbamic acid halides there are suitable, above all, the chlorides.

The benzenesulfonyl-ureas used as starting substances for the process of the invention may be unsubstituted at the side of the urea molecule opposite to the sulfonyl group or may be monoor preferably di-substituted. Since these substituents are split off during the reaction with amines, their nature can vary within wide limits. lnstead of benzenesulfonyl-ureas substituted by an alkyl, aryl, acy l or heterocyclic radical, there can likewise be used the Bis-(benzenesulfonyl)-ureas, which may carry a further substituent at one nitrogen atom, for example methyl. It is, for example, possible to treat such bis-(benzenesulfonyl)-ureas or N-benzenesulfonyl-N-acyl-ureas with amines of the formula RNH and to heat the salts so obtained to an elevated temperature, particularly to a temperature above 100C.

Furthermore, it is possible to start from ureas of the formula R -NH-CO-NH or from such ureas which are monoor, in particular di-substituted at the free nitrogen atom and to react these with benzenesulfonamides substituted by the grouping N-endome- 65 ylor N-nitro-ureas, N-endomethylenecyclohexylureas,,N'endomethylenecyclohexenylureas, N, N- diphenyl-ureas (in which case the two .phenyl radicals may be substituted and may be linked with one another directly or by means of a bridge member such as CH -NH O- or S,) N-methyl-N-phenylor N, N-dicyclohexyl-ureas as well as R -substituted cyclohexyl carbamoyl-imidazoles or triazoles.

Hydrolysis of the mentioned benzenesulfonyl-parabanic acids, benzenesulfonyl-isourea-ethers, benzenesulfonyl-thio-urea-ethers, benzenesulfonylisourea-esters or benzenesulfonyl-haloformic acid amidines is suitably carried out in an alkaline medium. Isourea-ethers and isourea-esters can be hydrolysed successfully in an acid medium, too.

The reaction with the benzenesulfonic halides with R -substituted ureas is suitably carried out by using basic condensing agents such as alkali metals, alkali amides or, preferably, hydrides in indifferent solvents.

The reaction of the sulfinic acids or sulfinic acid chlorides with hydroxy ureas can suitably be carried out in indifferent solvents. If the sulfinic acids or their alkali metals are used as starting substances, acid con- 5 densing agents such as for example thionyl chloride,

polyphosphoric acids, anhydrous phosphoric acid or sulfuric acid are added.

The sulfur atom in correspondingly substituted benzenesulfonyl-thioureas can be replaced by an oxygen atom, in known manner, for example with the aid of oxides or salts of heavy metals or likewise by applying oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid. I

Thioureas may also be desulfurized by treating them with phosgene or phosphorus pentachloride. Chloroformic acid amidines or carbodiimides obtained as intermediate products can be convertedinto the benzenesulfonyl-ureas by suitable processes such, for example, as saponification or addition of water.

The oxidation of the benzenesulfinylor. sulfenylureas can be carried out with the known oxidizing agents such as for example potassium permanganate in indifferent solvents.

Correspondingly substituted benzenesulfonyl-ureas, containing in the molecule an unsaturated bond, for example can be converted by hydrogenation for example with molecular hydrogen in the presence of a known hydration catalyst in the benzenesulfonyl-ureas according to the present invention.

The acylation of aminoethyl-benzenesulfonyl-ureas may be carried out either in one step, for example, by reaction of a correspondingly substituted benzoic acid halide, or it may be carried out in several steps. One example of the numerous possibilities of stepwise acylation is the reaction of aminoethyl-benzenesulfonylureas with 2-methoxy-benzoyl chloride and subsequent introduction of a halogen atom into the benzene nucleus of the benzamido group.

The sulfur atoms in correspondingly substituted thiobenzamido-ethyl-benzenesulfonyl-ureas or thiobenzamidoethylbenzenesulfonyl-thioureas can be replaced by oxygen atoms for example, with the aid of oxidizing agents such as hydrogen peroxide, sodium peroxide or other peroxide compounds.

Instead of the thiobenzamido-ethyl-benzenesulfonylureas the corresponding thiobenzamidoethyl-benzenesulfonyl-isothiourea-ethers, isourea-ethers or -esters, -parabanaic acids or thiobenzamidoethyl-benzenesulfonyl-haloformic acid amidines can be desulfurized by treatment with oxidizing agents in an acid or alkaline medium whereby simultaneously a desulfurization and a hydrolysis forming the sulfonyl-urea grouping occur and the benzamidoethyl-benzene-sulfonylureas are obtained.

10 synthesis other than that described.

As starting substances such compounds are used which contain a benzene nucleus being substituted by the group Instead of the thiobenzamido-ethyl-benzene-sul- CONHCH2CHZ fonylthioureas, compounds of the formula X DR f in para-position. C=N CHZ CH2 Q SO2 NH CS NH R1 AS examples for the part OR X wherein U has the meaning given above, can be converted by treatment with oxidizing agents in an acid or alkaline medium by simultaneous desulfuration and hy- Co drolysis into the corresponding benzamido-ethyl-benzenesulfonyl-ureas. 30' OR As regards the reaction conditions, the forms of realizing the process of the invention may, in general, vary within wide limits and can be adapted to each individof this substituent may be mentioned in particular the following:

-continued CI CI Cl Qco coco -'co CH, cm, oc,,H,(n awn,

Br Br Br -co Q co co c1 Q cocu, oc. .H CI ocmcua, OCH,

The preparation of the starting substances may be carried out according to generally known methods. Thus, for example benzenesulfonamides used as starting substances which are substituted in the benzene nucleus by the' radical can be obtained by reaction of the corresponding benzene compounds with chloro-sulfonic acid and subsequently with ammonia or by acylation of amino compounds of the formula with corresponding acid chlorides.

The benzenesulfonyl carbamic acid esters and -ureas used as starting material can be obtained for example from benzenesulfonamides and halogenoformic acid alkyl esters or potassium cyanate (KOCN).

The hypoglycemic action of the benzene-sulfonylurea derivatives described above could be determined by feeding them to rabbits in doses of mg/kg and determining the blood sugar value according to the known method by Hagedom-Jensen or by means of an auto-analyzer over a prolonged period of time.

Thus, it was found, for example, that 10 milligrams/- kilogram of N-[4-( B- 2-methoxy-5 -bromo-benzamido -ethyl)-benzenesulfonyl]-N-(2.5-endomethylene-cyclohexyl)-urea provoke, after 3 hours, a lowering of the blood sugar by 35 7c, after 24 hours 26 7c and after 48 hours 18 7c. i

In the same manner, 10 millilgrams of N-[4-(B- 2- methoxy-5 -c hlorobenzamido- -ethyl )benzene-sulfonyl ]-N 2 .5-endomethylene-cyclohexyl )-urea provoke after 3 hours a blood sugar lowering of 32 7:, after 24 hours of 43 7c, after 48 hours of 28 7c, and even after 72 hours of 14 7:, whereas the known N-[4-methylbenZene-sulfonyl]-N-butyl-urea, when administered to rabbits in doses of less than mg/kg, does not provoke a lowering of the blood sugar level.

The strong hypoglycemic action of the benzenesulfonyl-ureas of the present invention becomes more evident if the dose is further reduced. When N-[4-(B- 2 methoxy-S-bromo-benzam ido -ethyl )-benzenesul- OCH2CH=CH2 fonyl]-N-(2,5-endomethylene-cyclohexyl)-urea is ad ministered to rabbits in a dose of 0.01 mg/kg or N-[4- B- 2-methoxy-5-chloro-benzamido -ethyl )-benzenesulfonyl]-N 2.5-e ndomethylene-cyclohexyl urea is administered to rabbits in a dose of 0.06 mg/kg, or the N-[4-(,8- 2-methoxy-5-methylbenzamido ethyl )-be nzensulfonyl N 2. 5 -endom ethylenecyclohexyl)-urea is administered to rabbits in a dose of 0.06 mg/ kg, 21 distinct lowering of the blood sugar can still be observed.

The benzenesulfonyl-ureas described are preferably used for the manufacture of orally administrable pharmaceutical preparations for the lowering of the blood sugar level in the treatment of diabetes mellitus; they may be used as such or in the form of their physiologically tolerable salts or in the presence of substances which cause such salt formation. For the formation of salts there may be used, for example, alkaline agents such as alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates or bicarbonates or alkaline earth metal carbonates or bicarbonates.

The pharmaceutical preparations are advantageously in the form of tablets containing. in addition to the products of the present invention, the usual pharmaceutically suitable carriers such as talc, starch, lactose, tragacanth or magnesium stearate.

A pharmaceutical preparation containing one of the aforesaid benzenesulfonyl-ureas as the active substance, for example, a tablet or a powder, with or without the aforesaid carriers, is advantageously brought into a suitable unit dosage form. The dose chosen should comply with the activity of the benzenesulfonylurea used and the desired effect. Advantageously, the dosage per unit amounts to about 0.5 to mg, preferably 2 to 10 mg, but considerably higher or lower dosage units may also be used, which, if desired, are divided or multiplied prior to their administration.

The following Examples serve to illustrate the invention, but they are not intended to limit it thereto.

EXAMPLE 1 N- 4-( B- 2-methoxy-5-chlorobenzamido -ethyl benzenesulfonyl ]-N 2,5-endomethylene-cyclohexyl urea 9 tallization from methanol melts at 187 189C.

In analogous manner there are obtained: from N-[4-(B- 2-methoxy-4-ch'lorobenzamido -ethyl)- benzenesulfonyll-carbamic acid methyl ester (melting point l78 180C):

N-[4-( B- 2-methoxy-4-chlorobenzamido -ethyl benzenesulfonyl]-N'-(2.5-endomethylenecyclohexyl)- urea. melting point 203 205C (from methanol); from N-[4-( B- 2-ethoxy-5-ch1orobenzamido -ethyl )-benzenesulfonyl]-carbamic acid methyl ester (melting point 203 205C):

N-[4-( B- 2-ethoxy-S-chlorobenzamido -ethyl )-benzenesulfonyl ]-N'-( 2.5-endomethylenecyclohexyl)- urea, melting point 158 160C (from methanol); from N-[4-( B- 2-methoxy-5-bromobenzamido -ethyl)- benzenesulfonyl]carbamic acid methyl ester (melting point 197 199C):

N-[4-( B- 2-methoxy-5-bromobenzamido -ethyl benzenesulfonyl]-l\l'-(2.5-endomethylenecyclohexyl)- urea, melting point 171 172C (from methanol/- dimethylformamide); from N-[4-( B- 2-methoxy-S-methylbenzamido -ethyl benzenesulfonyl]-carbamic acid methyl ester (melting point 175 177C):

N-[4-( ,B- 2-methoxy-S-methylbenzamido -ethyl benzenesulfonyl]-N 2.5-endomethylenecyclohexyl urea, melting point 191 193C (from methanol/- dimethylformamide); from N-[4( B- 2.5-dimethoxy-benzamido -ethyl )-benzenesulfonyl]carbamic acid methyl ester (melting point 173 175C):

N-[4-( B- 2 S-dimethoxy-benzamido ethyl )-benzenesulfonyl]-N-(2.5-endomethylenecyclohexyl)- urea. melting point 163 165C (from methanol); from N-[4-( /3- 2-methoxybenzamido -ethyl )-benzenesulfonyl]-carbamic acid methyl ester (melting point 174 176C):

N[4-( B- 2-methoxybenzamido -ethyl )-benzenesulfonyl]-N-(2.5-endomethylenecyclohexyl)-urea. melting point 197 198C (from methanol); from N- 4-( B- 2methoxy-5-fluorobenzamido -ethyl benzenesulfonyll-carbamic acid methyl ester (melting point l71- 173C):

N-[ 4-( B- 2-methoxy-5-fluorobenzamido -ethy1)- benzenesulfonyl ]-N 2.5-endomethylenecyclohexyl urea, melting point 206 207C (from methanol/- dimethylformamide EXAMPLE 2 N- 4( ,B- 2-methoxy-5-fluorobenzamido -ethyl benzenesulfonyl ]-N 2.5-endomethylenecyclohexyl urea 6 g of 4-(B- 2-methoxy-5-fluorobenzamido ethyl)-benzenesulfonamide (melting point 167 169C are dissolved in 8.5 ml of 2N sodium hydroxide solution and 50 ml of acetone. and 2.5 g of 2.5 endomethylenecyclohexyl-isocyanate are added dropwise at 0 C. Stirring is continued for 3 hours, water and methanol is added. the whole is filtered from the undissolvcd matter and the filtrate is acidified with dilute hydrochloric acid. The N-[4 (,8 2-methoxy-5- fluorobcnzamido -ethyl )-benzenesulfonyl ]-N-( 2.5- endomethylenecyclohexyl)-urea which has precipi tated, melts after recrystallization from methanol/- dimethylformamide at 206 207C.

In analogous manner there is obtained: from 4-( B- -2-n-propoxy-5-chlorobenzamido -ethyl )-benzenesulfonamide (melting point 192 194C): N-[ 4-( ,B- 2-n-propoxy-S-chlorobenzamido -ethyl benzenesulfonyl]-N-(2.5-endomethylenecyclohexyl)- urea, melting point 171 173C (from methanol); from 4-( [3- 2-n-propoxy5-methylbenzamido -ethyl )-benzenesulfonamide (melting point 166 167C N- 4-( ,8- 2-n-propoxy5-methylbenzamido -ethyl)- benzenesulfonyl -N 2.5-endomethylenecyclohexyl urea, melting point 148 150C (from methanol); from 4( B- 2-methoxy-5-ethylbenzamido -ethyl )-ben- Zenesulfonamide (melting point 193 195C): N-[4-(B- 2-methoxy-5-ethylbenzamido -ethyl)-benzenesulfonyl]N'-(2.S-endomethylenecyclohexyl)- urea, melting point 162 164C (from methanol).

EXAMPLE 3 N-{4-( B- 2-methoxy- 5-chloro-benzamido -ethyl benzenesulfonyl]-N'-( 2 .5-endomethylenecyclohexyl urea 2 g of N-[4-(,8- 2-methoxy-5-chloro-benzamido ethyl)-benzenesulfonyl]-N'-(2.5-endomethylenecyclohexyl)-thiourea (prepared by boiling for several hours 4*(B- 2-methoxy-5-chl-orobenzamido -ethyl benzenesulfonamide and 2.5-endomethylenecyclohexyl mustard oil in acetone in the presence of potassium carbonate while stirring, melting point 158 160C (from dilute methanol)) are dissolved in about 10 ml of 2N sodium hydroxide solution and 5 ml of dioxane. After addition of 5 ml of hydrogen peroxide of 35 7c strength. the whole is heated for about 20 minutes in a water bath. After cooling it is acidified. There is obtained a crystalline precipitate which is filtered off with suction. dissolved in ammonia of about 1 7c strength and reprecipitated after filtration by acidification. The thus obtained crude N-[4-(B- 2-methoxy- 5-chlorobenzamido -ethyl )-be:nzene-sulfonyl l-( 2.5 endomethylenecyclohexyl)-urea melts after recrystallization from methanol at 186 188C.

EXAMPLE 4 N-[4-( ,8- 2-methoxy-5-chlorobenzamido ethyl benzenesulfonyl]-N 2 .5-endomethylenecyclohexyl urea a. l g. of N-[4-(B- 2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl]-N'-(2.5-endomethylenecyclohexyl)-thiourea (cf. Example 3) is dissolved in 50 ml of ethanol. After addition of 0.5 g of mercury oxide and a small amount of potassium carbonate, the whole is heated to 50 C for 4 hours while stirring. It is filtered, concentrated and crystallized from dilute methanol. The thus obtained N-[4-(B- 2-methoxy5-chlorobenzamido -ethyl)-benzenesulfonyl ]-N 2.5-endomethylenecylcohexyl )-isourea metehyl ether melts at 118 C.

12. 0.1 g of the product obtained according to 4a), is heated in 2 ml of dioxane and 10 ml of concentrated hydrochloric acid for 20 minutes in a vapour bath. The product which is obtained after pouring into water is filtered off with suction and recrystallized from dilute methanol. The N-[4-(B- 2-methoxy-5-chloro-ben zamido -ethyl )-benZenesu1fonyl]-N 2.5-endome- 1 1 thylenecyclohexyl)-urea thus prepared melts at 186 188C. The same product is obtained by alkaline saponification of the isourea ether prepared according to 4a) by heating for 1 hour with 2N sodium hydroxide solution in a vapour bath.

EXAMPLE N- 4-( ,8- Z-methoxy-S-chlorobenzamido -ethyl benzenesulfonyl -N 2.5-endomethylenecyclohexyl urea a. 0.8 g of endomethylenecyclohexyl-parabanic acid (melting point 111 l13C from dilute methanol) is dissolved in 30 ml of benzene, 0.4 g of trimethylamine and 1.6 g of 4-(B- Z-methoxy-S-chlorobenzamido ethyl)-benzenesulfonic acid chloride are added and heated to boil under reflux for 2 /2 hours. The whole is concentrated in vacuo, water is added to the residue obtained and it is triturated. The substance crystallizes after abandoning for some time. It is filtered off with suction. washed with water and recrystallized from methanol/dioxane. The thus obtained 1-[4-(B- 2- methoxy-5-chlorobenzamido -ethyl )-benzenesulfonyl ]-3-( 2.5-endomethylene-cyclohexyl )-parabanic acid melts at 227 229C.

b. The product obtained according to 5ais dissolved in a small amount of dioxane and 2N sodium hydroxide solution and the solution is heated in a vapour bath for 45 minutes. After cooling it is diluted with water and acidified. The precipitate obtained of N-[4-(,8- 2- methoxy-5-chloro-benzamido -ethyl )-benzenesulfonyl]-N-(2.5-endomethylenecyclohexy1)-urea melts after recrystallization from methanol/water at 186 188C.

EXAMPLE 6 N-[4-( ,8- 2-methoxy-5-chlorobenzamido -ethyl benzenesulfonyll-N 2.5-endomethylenecyclohexyl urea u. 3.1 g of N-Z.5-endomethylenecyclohexyl-urea are dissolved in pyridine, when introducing 7.4 g of 4-(B- Z-methoxy-S-chlorobenzamido -ethyl )-benzenesulfinyl chloride slight heating occurs. The clear solution is added after 10 minutes to a mixture of ice water and dilute hydrochloric acid, the precipitate thus formed is filtered off with suction, and stirred with ammonia of 0.5 7c strength. The amorphous precipitate is dissolved in acetone while hot. When cooling, the N-[4-(fi- 2- methoxy-5-chlorobenzamido -ethyl )-benzene-sulfinyl]-N'-( 2.S-endomethylenecyclohexyl )-urea crystallizes, having a melting point of 133 135C.

1). l g of the above-mentioned urea is dissolved in ml of dimethyl-formamide and an aqueous potassium permanganate solution in excess is added to the bath. After filtration of the pyrolusite. water and dilute hydrochloric acid is added and the precipitate which has formed is recrystallized. There is obtained N-[4-(,8- 2- methoxy-S-chlorobenzamido -ethyl )-benzenesulfonyl ]-N'-( 2 .S-endomethylenecyclohexyl )-urea melting at 187 189C.

What is claimed is:

l. A benzenesulfonyl-urea corresponding to the formula -continued Q SO:-NHCONHR' in which R represents lower alkyl or lower alkenyl,

X represents chlorine, lower alkyl, or lower alkoxy,

in 4- or 5-position to the carbonamide group,

R represents endomethylene-cyclohexenyl. endomethylene-cyclohexyl, endoethylenecyclohexyl, endoethylene-cyclohexenyl, and its salts of a pharrnaceutically acceptable base.

2. A compound as claimed in claim 1, wherein R is methyl, X is chloride in 5-position and R is 2.5- endomethylene-cyclohexyl.

3. A compound of the formula,

wherein R is methyl, X is bromine in 5-position and R is 2.5 endomethylene-cyclohexyl. 4. A compound of the formula.

wherein R is methyL X is fluorine in 5-position and R is 2.5 endomethylene cyclohexyl.

9. A compound as claimed in claim 1, wherein R is n-propyl, X is chlorine in 5-position and R is 2.5- endomethylene-cyclohexyl.

1 A d 11. A compound as claimed in claim 1, wherein R is i fi i heremRls methyl, x is ethyl in -p0sition and R 2.5- n-propyl. X 15 methyl 1n 5-pos1t10n and R 15 2.5- endomethylene cycloheXy] endomethylene cyclohexyl.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,917,690

DATED November 4, 1 975 lN\/ ENTOR(S) Weber et al.

:r is certified that error appears in the above-identified patent and that said Letters Patent Q are hereby corrected as shown below:

In the Heading between Items [63] and [52] insert:

--[30] Foreign Application Priority Data November 29, 1966 Germany F 50,793

July 13, 1967 Germany F 52 ,939-- Q Signed and Scaled this seventeenth Day Of February 1976 [SEAL] Attest: Q

RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'latents and Trademarks 

1. A BENZENESULFONYL-UREA CORRESPONDING TO THE FORMULA
 3. A compound of the formula,
 4. A compound of the formula,
 5. A compound as claimed in claim 1, wherein R is methyl, X is chlorine in 4-position and R1 is 2.5 endomethylene-cyclohexyl.
 6. A compound as claimed in claim 1, wherein R is ethyl, X is chlorine in 5-position and R1 is 2.5 endomethylene-cyclohexyl.
 7. A compound as claimed in claim 1, wherein R is methyl, X is methoxy in 5-position and R1 is 2.5-endomethylene cyclohexyl.
 8. A compound of the formula
 9. A compound as claimed in claim 1, wherein R is n-propyl, X is chlorine in 5-position and R1 is 2.5-endomethylene-cyclohexyl.
 10. A compound as claimed in claim 1, wherein R is n-propyl, X is methyl in 5-position and R1 is 2.5-endomethylene cyclohexyl.
 11. A compound as claimed in claim 1, wherein R is methyl, X is ethyl in 5-position and R1 is 2.5-endomethylene-cyclohexyl. 